Novel Phage Display Platforms to Overcome Colistin Resistance Project Summary Antibiotic resistance of bacterial pathogens poses a serious threat to our society. According to a recent CDC report, in the United States alone, there are over 2 million cases of infection and over 23,000 deaths every year that are caused by antibiotic-resistant strains of bacteria. Among these, colistin resistance of gram-negative bacteria demands urgent attention. Colistin is an old antibiotic first approved for clinical use several decades ago. It had been recently revived as the last hope antibiotic to treat carbapenem-resistant gram-negative infections. Colistin resistance are known to arise from cell envelope remodeling, ranging from subtle derivatizations of lipopolysaccharide (LPS) to total replacement of LPS with lipoproteins. Our recent work has shown that the remodeled cell envelope underlying colistin resistance can be targeted by screening novel peptide libraries on phage. Building on these preliminary studies, we propose to develop additional novel phage libraries that incorporate non-proteinogenic functional groups. Screening of these libraries against colistin-resistant bacteria is expected to reveal highly potent and specific binders for these deadly pathogens. We will further develop peptide-antibiotic conjugates for effective eradication of these colistin-resistant bacterial pathogens. The efficacy of the peptide-antibiotic conjugates will be assessed in vitro and in animal models. Research Strategy Page 1